Systems and methods for determining vessel compliance

ABSTRACT

The disclosure of the present application provides for systems and methods for determining a phasic change in a vessel and vessel compliance. In at least one exemplary method for determining a phasic change in a vessel, the method comprises the steps of introducing a device into a site within a vessel, operating the device in connection with two or more fluid injections in the vessel to obtain two or more conductance values, calculating a parallel conductance value and a total conductance value, and calculating a phasic change in at least one vessel parameter based in part upon the calculated parallel conductance value and the calculated total conductance value. In an exemplary method for determining vessel compliance, the method comprises, in part, the steps of calculating a first vessel parameter and a second vessel parameter based on at least two conductance values, calculating a change in vessel parameter based upon the first and second vessel parameters, and calculating vessel compliance based upon the relationship between the change in vessel parameter and a change in pressure during a cardiac cycle.

PRIORITY

This U.S. patent application is a continuation application of, andclaims priority to, U.S. patent application Ser. No. 12/426,033, filedApr. 17, 2009, which is a continuation-in-part application of, andclaims priority to, U.S. patent application Ser. No. 12/098,242, filedApr. 4, 2008, which is a continuation-in-part application of, and claimspriority to, U.S. patent application Ser. No. 11/891,981, filed Aug. 14,2007, which is a divisional application of, and claims priority to, U.S.patent application Ser. No. 10/782,149, filed Feb. 19, 2004, whichissued as U.S. Pat. No. 7,454,244 on Nov. 18, 2008, which claimspriority to U.S. Provisional Patent Application Ser. No. 60/449,266,filed Feb. 21, 2003, to U.S. Provisional Patent Application Ser. No.60/493,145, filed Aug. 7, 2003, and to U.S. Provisional PatentApplication Ser. No. 60/502,139, filed Sep. 11, 2003. The contents ofeach of these applications are hereby incorporated by reference in theirentirety into this disclosure.

BACKGROUND

The disclosure of the present application relates generally to medicaldiagnostics and treatment equipment, and in particular, to devices,systems, and methods for measuring luminal cross-sectional area of bloodvessels, heart valves and other hollow visceral organs. In addition, thedisclosure of the present application relates generally to systems andmethods for determining a phasic change in a vessel and vesselcompliance.

Coronary Heart Disease

Coronary heart disease is caused by atherosclerotic narrowing of thecoronary arteries. It is likely to produce angina pectoris, heart attackor both. Coronary heart disease caused 466,101 deaths in USA in 1997 andis the single leading cause of death in America today. Approximately, 12million people alive today have a history of heart attack, anginapectoris or both. The break down for males and females is 49% and 51%,respectively. This year, an estimated 1.1 million Americans will have anew or recurrent coronary attack, and more than 40% of the peopleexperiencing these attacks will die as a result. About 225,000 people ayear die of coronary attack without being hospitalized. These are suddendeaths caused by cardiac arrest, usually resulting from ventricularfibrillation. More than 400,000 Americans and 800,000 patientsworld-wide undergo a non-surgical coronary artery interventionalprocedure each year. Although only introduced in the 1990s, in somelaboratories intra-coronary stents are used in 90% of these patients.

Stents increase minimal coronary lumen diameter to a greater degree thanpercutaneous transluminal coronary angioplasty (PTCA) alone according tothe results of two randomized trials using the Palmaz-Schatz stent.These trials compared two initial treatment strategies: stenting aloneand PTCA with “stent backup” if needed. In the Stent Restenosis Study(STRESS) trial, there was a significant difference in successfulangiographic outcome in favor of stenting (96.1% vs. 89.6%).

Intravascular Ultrasound

Currently intravascular ultrasound is the method of choice to determinethe true diameter of the diseased vessel in order to size the stentcorrectly. The term “vessel,” as used herein, refers generally to anyhollow, tubular, or luminal organ, area, or space within a body. Thetomographic orientation of ultrasound enables visualization of the full360° circumference of the vessel wall and permits direct measurements oflumen dimensions, including minimal and maximal diameter andcross-sectional area. Information from ultrasound is combined with thatobtained by angiography. Because of the latticed characteristics ofstents, radiographic contrast material can surround the stent, producingan angiographic appearance of a large lumen, even when the stent strutsare not in full contact with the vessel wall. A large observationalultrasound study after angio-graphically guided stent deploymentrevealed an average residual plaque area of 51% in a comparison ofminimal stent diameter with reference segment diameter, and incompletewall apposition was frequently observed. In this cohort, additionalballoon inflations resulted in a final average residual plaque area of34%, even though the final angiographic percent stenosis was negative(20.7%). These investigators used ultrasound to guide deployment.

However, using intravascular ultrasound as mentioned above requires afirst step of advancement of an ultrasound catheter and then withdrawalof the ultrasound catheter before coronary angioplasty thereby addingadditional time to the stent procedure. Furthermore, it requires anultrasound machine. This adds significant cost and time and more risk tothe procedure.

Aortic Stenosis

Aortic Stenosis (AS) is one of the major reasons for valve replacementsin adult. AS occurs when the aortic valve orifice narrows secondary tovalve degeneration. The aortic valve area is reduced to one fourth ofits normal size before it shows a hemodynamic effect. Because the areaof the normal adult valve orifice is typically 3.0 to 4.0 cm², an area0.75-1.0 cm² is usually not considered severe AS. When stenosis issevere and cardiac output is normal, the mean trans-valvular pressuregradient is generally >50 mmHg. Some patients with severe AS remainasymptomatic, whereas others with only moderate stenosis developsymptoms. Therapeutic decisions, particularly those related tocorrective surgery, are based largely on the presence or absence ofsymptoms.

The natural history of AS in the adult consists of a prolonged latentperiod in which morbidity and mortality are very low. The rate ofprogression of the stenotic lesion has been estimated in a variety ofhemodynamic studies performed largely in patients with moderate AS.Cardiac catheterization and Doppler echocardiographic studies indicatethat some patients exhibit a decrease in valve area of 0.1-0.3 cm² peryear; the average rate of change is 0.12 cm² per year. The systolicpressure gradient across the valve may increase by as much as 10 to 15mmHg per year. However, more than half of the reported patients showedlittle or no progression over a 3-9 year period. Although it appearsthat progression of AS can be more rapid in patients with degenerativecalcific disease than in those with congenital or rheumatic disease, itis not possible to predict the rate of progression in an individualpatient.

Eventually, symptoms of angina, syncope, or heart failure develop aftera long latent period, and the outlook changes dramatically. After onsetof symptoms, average survival is <2-3 years. Thus, the development ofsymptoms identifies a critical point in the natural history of AS.

Many asymptomatic patients with severe AS develop symptoms within a fewyears and require surgery. The incidence of angina, dyspnea, or syncopein asymptomatic patients with Doppler outflow velocities of 4 m/s hasbeen reported to be as high as 38% after 2 years and 79% after 3 years.Therefore, patients with severe AS require careful monitoring fordevelopment of symptoms and progressive disease.

Indications for Cardiac Catheterization

In patients with AS, the indications for cardiac catheterization andangiography are to assess the coronary circulation (to confirm theabsence of coronary artery disease) and to confirm or clarify theclinical diagnosis of AS severity. If echocardiographic data are typicalof severe isolated. AS, coronary angiography may be all that is neededbefore aortic valve replacement (AVR), Complete left- and right-heartcatheterization may be necessary to assess the hemodynamic severity ofAS if there is a discrepancy between clinical and echocardiographic dataor evidence of associated valvular or congenital disease or pulmonaryhypertension.

The pressure gradient across a stenotic valve is related to the valveorifice area and transvalvular flow through Bernoulli's principle. Thus,in the presence of depressed cardiac output, relatively low pressuregradients are frequently obtained in patients with severe AS. On theother hand, during exercise or other high-flow states, systolicgradients can be measured in minimally stenotic valves. For thesereasons, complete assessment of AS requires (1) measurement oftransvalvular flow, (2) determination of the transvalvular pressuregradient, and (3) calculation of the effective valve area. Carefulattention to detail with accurate measurements of pressure and flow isimportant, especially in patients with low cardiac output or a lowtransvalvular pressure gradient.

Problems with Current Aortic Valve Area Measurements

Patients with severe AS and low cardiac output are often present withonly modest transvalvular pressure gradients (i.e., <30 mmHg). Suchpatients can be difficult to distinguish from those with low cardiacoutput and only mild to moderate AS. In both situations, the low-flowstate and low pressure gradient contribute to a calculated effectivevalve area that can meet criteria for severe AS. The standard valve areaformula (simplified Hakki formula which is valve area=cardiacoutput/[pressure gradient]^(1/2)) is less accurate and is known tounderestimate the valve area in low-flow states; under such conditions,it should be interpreted with caution. Although valve resistance is lesssensitive to flow than valve area, resistance calculations have not beenproved to be substantially better than valve area calculations.

In patients with low gradient stenosis and what appears to be moderateto severe AS, it may be useful to determine the transvalvular pressuregradient and calculate valve area and resistance during a baseline stateand again during exercise or pharmacological (i.e., dobutamine infusion)stress. Patients who do not have true, anatomically severe stenosisexhibit an increase in the valve area during an increase in cardiacoutput. In patients with severe AS, these changes may result in acalculated valve area that is higher than the baseline calculation butthat remains in the severe range, whereas in patients without severe AS,the calculated valve area will fall outside the severe range withadministration of dobutamine and indicate that severe AS is not present.

There are many other limitations in estimating aortic valve area inpatients with aortic stenosis using echocardiography and cardiaccatheterization. Accurate measurement of the aortic valve area inpatients with aortic stenosis can be difficult in the setting of lowcardiac output or concomitant aortic or mitral regurgitations.Concomitant aortic regurgitation or low cardiac output can overestimatethe severity of aortic stenosis. Furthermore, because of the dependenceof aortic valve area calculation on cardiac output, any under oroverestimation of cardiac output will cause inaccurate measurement ofvalve area. This is particularly important in patients with tricuspidregurgitation. Falsely measured aortic valve area could causeinappropriate aortic valve surgery in patients who do not need it.

Other Visceral Organs

Visceral organs such as the gastrointestinal tract and the urinary tractserve to transport luminal contents (fluids) from one end of the organto the other end or to an absorption site. The esophagus, for example,transports swallowed material from the pharynx to the stomach. Diseasesmay affect the transport function of the organs by changing the luminalcross-sectional area, the peristalsis generated by muscle, or bychanging the tissue components. For example, strictures in the esophagusand urethra constitute a narrowing of the organ where fibrosis of thewall may occur. Strictures and narrowing can be treated with distension,much like the treatment of plaques in the coronary arteries.

BRIEF SUMMARY

The disclosure of the present application provides for systems andmethods for determining a phasic change in a vessel and vesselcompliance. In at least one embodiment of a method for determining aphasic change in a vessel of the present disclosure, the methodcomprises the steps of introducing a device into a site within a vessel,the device comprising a pair of excitation electrodes positioned along aportion of the device and a pair of detection electrodes positionedalong a portion of the device, the pair of detection electrodescomprising two detection electrodes having a known distance from oneanother, the pair of detection electrodes physically positioned inbetween the pair of excitation electrodes along a portion of the device,operating the device in connection with two or more fluid injections inthe vessel at or near the site to obtain two or more conductance values,calculating at least one parallel conductance value and at least onetotal conductance value at or near the site based upon at least two ofthe two or more conductance values, and calculating a phasic change inthe at least one vessel parameter based upon the known distance of thetwo detection electrodes from one another, the calculated at least oneparallel conductance value, and the calculated at least one totalconductance value. In various embodiments, the at least one vesselparameter comprises at least one vessel diameter and/or at least onevessel cross-sectional area. In another embodiment, the step ofcalculating a phasic change in the at least one vessel parameter isfurther based upon a mean conductivity of a fluid present within thevessel.

In at least one embodiment of a method for determining a phasic changein a vessel of the present disclosure, the fluid present within thevessel comprises blood. In an exemplary embodiment, the step ofcalculating a phasic change in the at least one vessel parameterconsiders a constant representing a mean conductivity of a fluid presentwithin the vessel, and in at least one embodiment, the constant may varyby no more than 10%.

In at least one embodiment of a method for determining a phasic changein a vessel of the present disclosure, the method further comprises thestep of determining the extent of vessel disease based upon thecalculated phasic change in the at least one vessel parameter. Invarious embodiments, the extent of vessel disease is determined to berelatively low if the calculated phasic change in the at least onevessel parameter is relatively high, is determined to be relatively highif the calculated phasic change in the at least one vessel parameter isrelatively low, and/or is determined to include vessel calcification ifthe calculated phasic change in the at least one vessel parameter iszero. In an exemplary embodiment, the extent of vessel disease includesa vessel disease selected from the group consisting of atherosclerosis,vessel calcification, degenerative calcific disease, congenital heartdisease, rheumatic disease, and coronary artery disease.

In at least one embodiment of a method for determining a phasic changein a vessel of the present disclosure, the calculated at least oneparallel conductance value used in the step of calculating a phasicchange in the at least one vessel parameter is a mean parallelconductance value. In another embodiment, the site comprises a siteselected from the group consisting of a body lumen, a body vessel, abiliary tract, and an esophagus. In yet another embodiment, the step ofproviding electrical current flow for a period of time to the sitethrough the device. In an additional embodiment, the device comprises adevice selected from the group consisting of an impedance catheter, aguide catheter, a guide wire, and a pressure wire.

In at least one embodiment of a method for determining a phasic changein a vessel of the present disclosure, the device used further comprisesan inflatable balloon positioned along a portion of the device, and themethod further comprises the step of inflating the balloon to breakupmaterials causing stenosis at the site. In an additional embodiment, thedevice further comprises a stent positioned over the balloon, the stentcapable of being distended to a desired size and implanted into thesite, and the method further comprises the steps of distending the stentby inflating the balloon, and releasing and implanting the stent intothe site. In at least one embodiment, the balloon is inflated using afluid, and the method further comprises the steps of providingelectrical current to the fluid filling the balloon at various degreesof balloon distension, measuring a conductance of the fluid inside theballoon, and calculating a cross-sectional area of the balloon lumen.

In at least one embodiment of a method for determining a phasic changein a vessel of the present disclosure, the device used further comprisesa stent positioned along a portion of the device, the stent capable ofbeing distended to a desired size and implanted into the site. In anexemplary embodiment, the method further comprising the steps ofpositioning the stent at or near the site, distending the stent, andreleasing and implanting the stent into the site. In at least oneembodiment, the two or more conductance values are retrieved by a dataacquisition and processing system operably connected to the device, andthe data acquisition and processing system is operable to calculate aphasic change in the at least one vessel parameter. In anotherembodiment, the device comprises at least one suction/infusion port incommunication with at least one lumen of the device, whereby the two ormore fluid injections occur via the at least one suction/infusion port.

In at least one embodiment of a method for determining a phasic changein a vessel of the present disclosure, the device used comprises acatheter having a lumen, a proximal end, and a distal end, and the pairof excitation electrodes and the pair of detection electrodes arepositioned along a portion of the device at or near the distal end ofthe device. In another embodiment, the pair of excitation electrodes andthe pair of detection electrodes have insulated electrical wireconnections that run through the lumen and proximal end of the catheter.In at least one embodiment, the calculated phasic change is indicativeof a phasic change throughout a cardiac cycle.

In at least one embodiment of a method for determining a phasic changein a vessel of the present disclosure, the method comprises the step ofintroducing a device into a site within a vessel, the device comprisinga catheter having a lumen, a proximal end, and a distal end, a pair ofexcitation electrodes positioned along a portion of the device at ornear the distal end of the device, and a pair of detection electrodespositioned along a portion of the device at or near the distal end ofthe device, the pair of detection electrodes comprising two detectionelectrodes having a known distance from one another, the pair ofdetection electrodes physically positioned in between the pair ofexcitation electrodes along a portion of the device, operating thedevice in connection with two or more fluid injections in the vessel ator near the site to obtain two or more conductance values, wherein thetwo or more conductance values are retrieved by a data acquisition andprocessing system operably connected to the device, calculating at leastone parallel conductance value and at least one total conductance valueat or near the site based upon at least two of the two or moreconductance values, calculating a phasic change in the at least onevessel parameter using the data acquisition and processing system basedupon the known distance of the two detection electrodes from oneanother, the calculated at least one parallel conductance value, and thecalculated at least one total conductance value, and determining theextent of vessel disease based upon the calculated phasic change in theat least one vessel parameter, wherein the extent of vessel disease isdetermined to be relatively low if the calculated phasic change in theat least one vessel parameter is relatively high, and wherein the extentof vessel disease is determined to be relatively high if the calculatedphasic change in the at least one vessel parameter is relatively low.

In at least one method for determining vessel compliance of the presentdisclosure, the method comprises the steps of introducing a device intoa site within a vessel, the device comprising a pair of excitationelectrodes positioned along a portion of the device, and a pair ofdetection electrodes positioned along a portion of the device, the pairof detection electrodes comprising two detection electrodes having aknown distance from one another, the pair of detection electrodesphysically positioned in between the pair of excitation electrodes,operating the device in connection with two or more fluid injections inthe vessel at or near the site to obtain two or more conductance values,each of the two or more fluid injections having a known conductivity,calculating a first vessel parameter of the site based on at least twoof the two or more conductance values and the conductivities of at leasttwo of the two or more fluid injections, calculating a second vesselparameter of the site based on at least two of the two or moreconductance values and the conductivities of at least two of the two ormore fluid injections, calculating a change in vessel parameter basedupon the first vessel parameter and the second vessel parameter, andcalculating vessel compliance based upon the relationship between thechange in vessel parameter and a change in pressure during a cardiaccycle. In another embodiment, the method further comprises the step ofdetermining the extent of vessel disease based upon the calculatedvessel compliance. In various embodiments, the extent of vessel diseaseis determined to be relatively low if the calculated vessel complianceis relatively high, is determined to be relatively high if thecalculated vessel compliance is relatively low, an/or is determined toinclude vessel calcification if the calculated vessel compliance iszero. In at least one embodiment, the extent of vessel disease includesa vessel disease selected from the group consisting of atherosclerosis,vessel calcification, degenerative calcific disease, congenital heartdisease, rheumatic disease, and coronary artery disease.

In at least one method for determining vessel compliance of the presentdisclosure, the two or more conductance values are retrieved by a dataacquisition and processing system operably connected to the device, andthe data acquisition and processing system is operable to calculatevessel compliance. In another embodiment, the change in pressure duringa cardiac cycle has a constant value for a patient. In variousembodiments, the first vessel parameter and the second vessel parametereach comprise a vessel diameter, and the change in vessel parametercomprises a change in vessel diameter, or the first vessel parameter andthe second vessel parameter each comprise a vessel cross-sectional area,and the change in vessel parameter comprises a change in vesselcross-sectional area.

In at least one method for determining vessel compliance of the presentdisclosure, the method further comprises the step of calculating anindex of compliance based in part upon a difference between the firstvessel parameter and the second vessel parameter divided by the firstvessel parameter. In an exemplary embodiment, the first vessel parametercomprises a first vessel systolic diameter, the second vessel parametercomprises a second vessel diastolic diameter, and the first vesselsystolic diameter and the second vessel diastolic diameter arerepresentative of a single vessel. In another embodiment, the firstvessel parameter comprises a first vessel systolic cross-sectional area,the second vessel parameter comprises a second vessel diastoliccross-sectional area, and the first vessel systolic cross-sectional areaand the second vessel diastolic cross-sectional area are representativeof a single vessel.

In at least one method for determining vessel compliance of the presentdisclosure, the device used comprises a device selected from the groupconsisting of an impedance catheter, a guide catheter, a guide wire, anda pressure wire. In at least one embodiment, the device furthercomprises an inflatable balloon positioned along a portion of thedevice, and the method further comprises the step of inflating theballoon to breakup materials causing stenosis at the site. In anotherembodiment, the device further comprises a stent positioned over theballoon, the stent capable of being distended to a desired size andimplanted into the site, and the method further comprises the steps ofdistending the stent by inflating the balloon, and releasing andimplanting the stent into the site. In an additional embodiment, theballoon is inflated using a fluid, and the method further comprises thesteps of providing electrical current to the fluid filling the balloonat various degrees of balloon distension, measuring a conductance of thefluid inside the balloon, and calculating a cross-sectional area of theballoon lumen. In yet an additional embodiment, the device usedcomprises at least one suction/infusion port in communication with atleast one lumen of the device, whereby the two or more fluid injectionsoccur via the at least one suction/infusion port.

In an at least one method for determining vessel compliance of thepresent disclosure, the method comprises the steps of introducing adevice into a site within a vessel, the device comprising a pair ofexcitation electrodes and a pair of detection electrodes positionedtherebetween, operating the device to obtain two or more conductancevalues, calculating a change in cross-sectional area based in part uponthe two or more conductance values, and calculating vessel compliancebased upon the relationship between the change in cross-sectional areaand a change in pressure during a cardiac cycle.

In at least one embodiment of a system for determining a phasic changein a vessel of the present disclosure, the system comprises a devicecapable of acquiring conductance data, the device comprising a pair ofexcitation electrodes positioned along a portion of the device and apair of detection electrodes positioned along a portion of the device,the pair of detection electrodes comprising two detection electrodeshaving a known distance from one another, the pair of detectionelectrodes physically positioned in between the pair of excitationelectrodes along a portion of the device, an injection source forinjecting one or more solutions through the device to a target site, acurrent source for providing current to the device, and a dataacquisition and processing system that receives conductance data fromthe device, wherein the data acquisition and processing system isoperable to calculate a phasic change in the at least one vesselparameter based upon the known distance of the two detection electrodesfrom one another, and a calculated at least one parallel conductancevalue and a calculated at least one total conductance value, each valuecalculated based upon the conductance data acquired from the device.

In at least one embodiment of a system for determining vessel complianceof the present disclosure, the system comprises a device capable ofacquiring conductance data, the device comprising a pair of excitationelectrodes positioned along a portion of the device and a pair ofdetection electrodes positioned along a portion of the device, the pairof detection electrodes comprising two detection electrodes having aknown distance from one another, the pair of detection electrodesphysically positioned in between the pair of excitation electrodes alonga portion of the device, an injection source for injecting one or moresolutions through the device to a target site, a current source forproviding current to the device and a data acquisition and processingsystem that receives conductance data from the device, wherein the dataacquisition and processing system is operable to calculate vesselcompliance based upon a calculated change in vessel parameter based upona calculated first vessel parameter and a calculated second vesselparameter, the calculated first vessel parameter and a calculated secondvessel parameter calculated based upon the conductance data acquiredfrom the device, and a calculated relationship between the calculatedchange in vessel parameter and a change in pressure during a cardiaccycle.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates a balloon catheter having impedance measuringelectrodes supported in front of the stenting balloon;

FIG. 1B illustrates a balloon catheter having impedance measuringelectrodes within and in front of the balloon;

FIG. 1C illustrates a catheter having an ultrasound transducer withinand in front of balloon;

FIG. 1D illustrates a catheter without a stenting balloon;

FIG. 1E illustrates a guide catheter with wire and impedance electrodes;

FIG. 1F illustrates a catheter with multiple detection electrodes;

FIG. 2A illustrates a catheter in cross-section proximal to the locationof the sensors showing the leads embedded in the material of the probe;

FIG. 2B illustrates a catheter in cross-section proximal to the locationof the sensors showing the leads run in separate lumens;

FIG. 3 is a schematic of one embodiment of the system showing a cathetercarrying impedance measuring electrodes connected to the dataacquisition equipment and excitation unit for the cross-sectional areameasurement;

FIG. 4A show the detected filtered voltage drop as measured in the bloodstream before and after injection of 1.5% NaCl solution;

FIG. 4B shows the peak-to-peak envelope of the detected voltage shown inFIG. 4A;

FIG. 5A show the detected filtered voltage drop as measured in the bloodstream before and after injection of 0.5% NaCl solution;

FIG. 5B shows the peak-to-peak envelope of the detected voltage shown inFIG. 5A;

FIG. 6 illustrates balloon distension of the lumen of the coronaryartery;

FIG. 7 illustrates balloon distension of a stent into the lumen of thecoronary artery;

FIG. 8A illustrates the voltage recorded by a conductance catheter witha radius of 0.55 mm for various size vessels (vessel radii of 3.1, 2.7,2.3, 1.9, 1.5 and 0.55 mm for the six curves, respectively) when a 0.5%NaCl bolus is injected into the treatment site;

FIG. 8B illustrates the voltage recorded by a conductance catheter witha radius of 0.55 mm for various size vessels (vessel radii of 3.1, 2.7,2.3, 1.9, 1.5 and 0.55 mm for the six curves, respectively) when a 1.5%NaCl bolus is injected into the treatment site;

FIG. 9 shows a photograph of a segment of swine carotid artery used forperforming ex-vivo validation of the algorithm of the presentdisclosure;

FIG. 10 shows ex-vivo data using a two-injection method of the presentdisclosure;

FIG. 11 shows ex-vivo data using a pull back method of the presentdisclosure;

FIG. 12 shows in-vivo data using a two-injection method of the presentdisclosure as compared to the IVUS method;

FIG. 13A shows phasic changes of total conductance showing cardiac andrespiratory changes as referenced herein;

FIG. 13B shows the phasic changes of diameter for an exemplary normalcoronary artery; and

FIG. 13C shows the phasic changes of diameter for an exemplaryatherosclerotic coronary artery.

DETAILED DESCRIPTION

The disclosure of the present application provides devices, systems, andmethods to obtain accurate measures of the luminal cross-sectional areaof organ stenosis within acceptable limits to enable accurate andscientific stent sizing and placement in order to improve clinicaloutcomes by avoiding under or over deployment and under or over sizingof a stent which can cause acute closure or in-stent re-stenosis. Forthe purposes of promoting an understanding of the principles of thepresent disclosure, reference will now be made to the embodimentsillustrated in the drawings, and specific language will be used todescribe the same. It will nevertheless be understood that no limitationof the scope of the present disclosure is thereby intended.

In one embodiment, an angioplasty or stent balloon includes impedanceelectrodes supported by the catheter in front of the balloon. Theseelectrodes enable the immediate measurement of the cross-sectional areaof the vessel during the balloon advancement. This provides a directmeasurement of non-stenosed area and allows the selection of theappropriate stent size. In one approach, error due to the loss ofcurrent in the wall of the organ and surrounding tissue is corrected byinjection of two solutions of NaCl or other solutions with knownconductivities. In another embodiment impedance electrodes are locatedin the center of the balloon in order to deploy the stent to the desiredcross-sectional area. These embodiments and procedures substantiallyimprove the accuracy of stenting and the outcome and reduce the cost.

Other embodiments make diagnosis of valve stenosis more accurate andmore scientific by providing a direct accurate measurement ofcross-sectional area of the valve annulus, independent of the flowconditions through the valve. Other embodiments improve evaluation ofcross-sectional area and flow in organs like the gastrointestinal tractand the urinary tract.

Embodiments of the disclosure of the present application overcome theproblems associated with determination of the size (cross-sectionalarea) of luminal organs, such as, for example, in the coronary arteries,carotid, femoral, renal and iliac arteries, aorta, gastrointestinaltract, urethra and ureter. Embodiments also provide methods forregistration of acute changes in wall conductance, such as, for example,due to edema or acute damage to the tissue, and for detection of musclespasms/contractions.

As described below, in one preferred embodiment, there is provided anangioplasty catheter with impedance electrodes near the distal end 19 ofthe catheter (i.e., in front of the balloon) for immediate measurementof the cross-sectional area of a vessel lumen during balloonadvancement. This catheter includes electrodes for accurate detection oforgan luminal cross-sectional area and ports for pressure gradientmeasurements. Hence, it is not necessary to change catheters such aswith the current use of intravascular ultrasound. In one preferredembodiment, the catheter provides direct measurement of the non-stenosedarea, thereby allowing the selection of an appropriately sized stent. Inanother embodiment, additional impedance electrodes may be incorporatedin the center of the balloon on the catheter in order to deploy thestent to the desired cross-sectional area. The procedures describedherein substantially improve the accuracy of stenting and improve thecost and outcome as well.

In another embodiment, the impedance electrodes are embedded within acatheter to measure the valve area directly and independent of cardiacoutput or pressure drop and therefore minimize errors in the measurementof valve area. Hence, measurements of area are direct and not based oncalculations with underlying assumptions. In another embodiment,pressure sensors can be mounted proximal and distal to the impedanceelectrodes to provide simultaneous pressure gradient recording.

Catheter

Exemplary impedance or conductance catheters for use within thedisclosure of the present application are illustrated in FIGS. 1A-1F.With reference to the exemplary embodiment shown in FIG. 1A, four wireswere threaded through one of the 2 lumens of a 4 Fr catheter. Here,electrodes 26 and 28, are spaced 1 mm apart and form the inner(detection) electrodes. Electrodes 25 and 27 are spaced 4-5 mm fromeither side of the inner electrodes and form the outer (excitation)electrodes. It can be appreciated that catheters of various sizes andincluding electrodes positioned in various locations may be useful inaccordance with the present disclosure.

In one approach, dimensions of a catheter to be used for any givenapplication depend on the optimization of the potential field usingfinite element analysis described below. For small organs, or inpediatric patients the diameter of the catheter may be as small as 0.3mm. In large organs the diameter may be significantly larger dependingon the results of the optimization based on finite element analysis. Theballoon size will typically be sized according to the preferreddimension of the organ after the distension. The balloon may be made ofmaterials, such as, for example, polyethylene, latex,polyestherurethane, or combinations thereof. The thickness of theballoon will typically be on the order of a few microns. The catheterwill typically be made of PVC or polyethylene, though other materialsmay equally well be used. The excitation and detection electrodestypically surround the catheter as ring electrodes but they may also bepoint electrodes or have other suitable configurations. These electrodesmay be made of any conductive material, preferably of platinum iridiumor a carbon-coasted surface to avoid fibrin deposits. In a preferredembodiment, the detection electrodes are spaced with 0.5-1 mm betweenthem and with a distance between 4-7 mm to the excitation electrodes onsmall catheters. The dimensions of the catheter selected for a treatmentdepend on the size of the vessel and are preferably determined in parton the results of finite element analysis, described below. On largecatheters, for use in larger vessels and other visceral hollow organs,the electrode distances may be larger.

Referring to FIGS. 1A, 1B, 1C, and 1D, several embodiments of thecatheters are illustrated. The catheters shown contain to a varyingdegree different electrodes, number and optional balloon(s). Withreference to the embodiment shown in FIG. 1A, there is shown animpedance catheter 20 with 4 electrodes 25, 26, 27, and 28 placed closeto the tip 19 of the catheter. Proximal to these electrodes is anangiography or stenting balloon 30 capable of being used for treatingstenosis. Electrodes 25 and 27 are excitation electrodes, whileelectrodes 26 and 28 are detection electrodes, which allow measurementof cross-sectional area during advancement of the catheter, as describedin further detail below. The portion of the catheter 20 within balloon30 includes an infusion port 35 and a pressure port 36.

The catheter 20 may also advantageously include several miniaturepressure transducers (not shown) carried by the catheter or pressureports for determining the pressure gradient proximal at the site wherethe cross-sectional area is measured. The pressure is preferablymeasured inside the balloon and proximal, distal to and at the locationof the cross-sectional area measurement, and locations proximal anddistal thereto, thereby enabling the measurement of pressure recordingsat the site of stenosis and also the measurement of pressure-differencealong or near the stenosis. In one embodiment, shown in FIG. 1A,catheter 20 advantageously includes pressure port 90 and pressure port91 proximal to or at the site of the cross-sectional measurement forevaluation of pressure gradients. As described below with reference toFIGS. 2A, 2B, and 3, in one embodiment, the pressure ports are connectedby respective conduits in the catheter 20 to pressure sensors in thedata acquisition system 100. Such pressure sensors are well known in theart and include, for example, fiber-optic systems, miniature straingauges, and perfused low-compliance manometry.

In one embodiment, a fluid-filled silastic pressure-monitoring catheteris connected to a pressure transducer. Luminal pressure can be monitoredby a low compliance external pressure transducer coupled to the infusionchannel of the catheter. Pressure transducer calibration was carried outby applying 0 and 100 mmHg of pressure by means of a hydrostatic column.

In one embodiment, shown in FIG. 1B, the catheter 39 includes anotherset of excitation electrodes 40, 41 and detection electrodes 42, 43located inside the angioplastic or stenting balloon 30 for accuratedetermination of the balloon cross-sectional area during angioplasty orstent deployment. These electrodes are in addition to electrodes 25, 26,27, and 28.

In one embodiment, the cross-sectional area may be measured using atwo-electrode system. In another embodiment, illustrated in FIG. 1F,several cross-sectional areas can be measured using an array of 5 ormore electrodes. Here, the excitation electrodes 51, 52, are used togenerate the current while detection electrodes 53, 54, 55, 56, and 57are used to detect the current at their respective sites.

The tip of the catheter can be straight, curved or with an angle tofacilitate insertion into the coronary arteries or other lumens, suchas, for example, the biliary tract. The distance between the balloon andthe electrodes is usually small, in the 0.5-2 cm range but can be closeror further away, depending on the particular application or treatmentinvolved.

In another embodiment, shown in FIG. 1C, the catheter 21 has one or moreimaging or recording devices, such as, for example, ultrasoundtransducers 50 for cross-sectional area and wall thickness measurements.As shown in this embodiment, the transducers 50 are located near thedistal tip 19 of the catheter 21.

FIG. 1D illustrates an embodiment of impedance catheter 22 without anangioplastic or stenting balloon. The catheter in this exemplaryembodiment also possesses an infusion or injection port 35 locatedproximal relative to the excitation electrode 25 and pressure port 36.

With reference to the embodiment shown in FIG. 1E, the electrodes 25,26, 27, and 28 can also be built onto a wire 18, such as, for example, apressure wire, and inserted through a guide catheter 23 where theinfusion of bolus can be made through the lumen of the guide catheter37.

With reference to the embodiments shown in FIGS. 1A, 1B, 1C, 1D, 1E, and1F, the impedance catheter advantageously includes optional ports 35,36, and 37 for suction of contents of the organ or infusion of fluid.The suction/infusion ports 35, 36, and 37 can be placed as shown withthe balloon or elsewhere both proximal or distal to the balloon on thecatheter. The fluid inside the balloon can be any biologicallycompatible conducting fluid. The fluid to inject through the infusionport or ports can be any biologically compatible fluid but theconductivity of the fluid is selected to be different from that of blood(e.g., NaCl).

In another embodiment (not illustrated), the catheter may contain anextra channel for insertion of a guide wire to stiffen the flexiblecatheter during the insertion or data recording. In yet anotherembodiment (not illustrated), the catheter may include a sensor formeasurement of the flow of fluid in the body organ.

System for Determining Cross-Sectional Area and Pressure Gradient

The operation of the impedance catheter 20 is as follows: With referenceto the embodiment shown in FIG. 1A for electrodes 25, 26, 27, and 28,conductance of current flow through the organ lumen and organ wall andsurrounding tissue is parallel; i.e.,

$\begin{matrix}{{G\left( {z,t} \right)} = {\frac{{{CSA}\left( {z,t} \right)} \cdot C_{b}}{L} + {G_{p}\left( {z,t} \right)}}} & \left\lbrack {1a} \right\rbrack\end{matrix}$where G_(p)(z,t) is the effective conductance of the structure outsidethe bodily fluid (organ wall and surrounding tissue) at a givenposition, z, along the long axis of the organ at a given time, t, andC_(b) is the electrical conductivity of the bodily fluid which for bloodgenerally depends on the temperature, hematocrit and orientation anddeformation of blood cells, and L is the distance between the detectionelectrodes. Equation [1a] can be rearranged to solve for cross sectionalarea CSA(t), with a correction factor, α, if the electric field isnon-homogeneous, as

$\begin{matrix}{{{CSA}\left( {z,t} \right)} = {\frac{L}{\alpha\; C_{b}}\left\lbrack {{G\left( {z,t} \right)} - {G_{p}\left( {z,t} \right)}} \right\rbrack}} & \left\lbrack {1b} \right\rbrack\end{matrix}$where α would be equal to 1 if the field were completely homogeneous.The parallel conductance, G_(p), is an offset error that results fromcurrent leakage. G_(p) would equal 0 if all of the current were confinedto the blood and hence would correspond to the cylindrical model givenby Equation [10]. In one approach, finite element analysis is used toproperly design the spacing between detection and excitation electrodesrelative to the dimensions of the vessel to provide a nearly homogenousfield such that a can be considered equal to 1. Our simulations showthat a homogenous or substantially homogenous field is provided by (1)the placement of detection electrodes substantially equidistant from theexcitation electrodes and (2) maintaining the distance between thedetection and excitation electrodes substantially comparable to thevessel diameter. In one approach, a homogeneous field is achieved bytaking steps (1) and/or (2) described above so that α is equals 1 in theforegoing analysis.

At any given position, z, along the long axis of organ and at any giventime, t, in the cardiac cycle, G_(p) is a constant. Hence, twoinjections of different concentrations and/or conductivities of NaClsolution give rise to two equations:C ₁·CSA(z,t)+L·G _(p)(z,t)=L·G ₁(z,t)  [2]andC ₂·CSA(z,t)+L·G _(p)(z,t)=L·C ₂(z,t)  [3]which can be solved simultaneously for CSA and G_(p) as

$\begin{matrix}{{{{CSA}\left( {z,t} \right)} = {L\frac{\left\lbrack {{G_{2}\left( {z,t} \right)} - {G_{1}\left( {z,t} \right)}} \right\rbrack}{\left\lbrack {C_{2} - C_{1}} \right\rbrack}}}{and}} & \lbrack 4\rbrack \\{{G_{p}\left( {z,t} \right)} = \frac{\left\lbrack {{C_{2} \cdot {G_{1}\left( {z,t} \right)}} - {C_{1} \cdot {G_{2}\left( {z,t} \right)}}} \right\rbrack}{\left\lbrack {C_{2} - C_{1}} \right\rbrack}} & \lbrack 5\rbrack\end{matrix}$where subscript “1” and subscript “2” designate any two injections ofdifferent NaCl concentrations and/or conductivities. For each injectionk, C_(k) gives rise to G_(k) which is measured as the ratio of the rootmean square of the current divided by the root mean square of thevoltage. The C_(k) is typically determined through in vitro calibrationfor the various NaCl concentrations and/or conductivities. Theconcentration of NaCl used is typically on the order of 0.45 to 1.8%.The volume of NaCl solution is typically about 5 ml, but sufficient todisplace the entire local vascular blood volume momentarily. The valuesof CSA(t) and G_(p)(t) can be determined at end-diastole or end-systole(i.e., the minimum and maximum values) or the mean thereof.

Once the CSA and G_(p) of the vessel are determined according to theabove embodiment, rearrangement of Equation [1a] allows the calculationof the electrical conductivity of blood in the presence of blood blow as

$\begin{matrix}{C_{b} = {\frac{L}{{CSA}\left( {z,t} \right)}\left\lbrack {{G\left( {z,t} \right)} - {G_{p}\left( {z,t} \right)}} \right\rbrack}} & \lbrack 6\rbrack\end{matrix}$In this way, Equation [1b] can be used to calculate the CSA continuously(temporal variation as for example through the cardiac cycle) in thepresence of blood.

In one approach, a pull or push through is used to reconstruct thevessel along its length. During a long injection (e.g., 10-15 s), thecatheter can be pulled back or pushed forward at constant velocity, U.Equation [1b] can be expressed as

$\begin{matrix}{{{CSA}\left( {{U \cdot t},t} \right)} = {\frac{L}{C_{b}}\left\lbrack {{G\left( {{U \cdot t},t} \right)} - {G_{p}\left( {U \cdot \left( {t,t} \right)} \right\rbrack}} \right.}} & \lbrack 7\rbrack\end{matrix}$where the axial position, z, is the product of catheter velocity, U, andtime, t; i.e., z=U·t.

For the two injections, denoted by subscript “1” and subscript “2”,respectively, different time points T₁, T₂, etc., may be considered suchthat equation [7] can be written as

$\begin{matrix}{{{CSA}_{1}\left( {{U \cdot T_{1}},t} \right)} = \;{\frac{L}{C_{1}}\left\lbrack {{G_{1}\left( {{U \cdot T_{1}},t} \right)} - {G_{p\; 1}\left( {{U \cdot T_{1}},t} \right)}} \right\rbrack}} & \left\lbrack {8a} \right\rbrack \\{{{{CSA}_{1}\left( {{U \cdot T_{1}},t} \right)} = \;{\frac{L}{C_{2}}\left\lbrack {{G_{2}\left( {{U \cdot T_{1}},t} \right)} - {G_{p\; 1}\left( {{U \cdot T_{1}},t} \right)}} \right\rbrack}}{and}} & \left\lbrack {8b} \right\rbrack \\{{{CSA}_{2}\left( {{U \cdot T_{2}},t} \right)} = \;{\frac{L}{C_{1}}\left\lbrack {{G_{1}\left( {{U \cdot T_{2}},t} \right)} - {G_{p\; 2}\left( {{U \cdot T_{2}},t} \right)}} \right\rbrack}} & \left\lbrack {9a} \right\rbrack \\{{{CSA}_{2}\left( {{U \cdot T_{2\;}},t} \right)} = \;{\frac{L}{C_{2}}\left\lbrack {{G_{2}\left( {{U \cdot T_{2}},t} \right)} - {G_{p\; 2}\left( {{U \cdot T_{2}},t} \right)}} \right\rbrack}} & \left\lbrack {9b} \right\rbrack\end{matrix}$and so on. Each set of equations [8a], [8b] and [9a], [9b], etc. can besolved for CSA₁, G_(p1) and CSA₂, G_(p2), respectively. Hence, the CSAat various time intervals may be measured and hence of differentpositions along the vessel to reconstruct the length of the vessel. Inone embodiment, the data on the CSA and parallel conductance as afunction of longitudinal position along the vessel can be exported froman electronic spreadsheet, such as, for example, an Excel file, toAutoCAD where the software uses the coordinates to render a profile onthe monitor.

For example, in one exemplary approach, the pull back reconstruction wasmade during a long injection where the catheter was pulled back atconstant rate by hand. The catheter was marked along its length suchthat the pull back was made at 2 mm/sec. Hence, during a 10 secondinjection, the catheter was pulled back about 2 cm. The data wascontinuously measured and analyzed at every two second interval; i.e.,at every 4 mm. Hence, six different measurements of CSA and G_(p) weremade which were used to reconstruct the CSA and G_(p) along the lengthof the 2 cm segment, namely at 0 mm, 4 mm, 8 mm, 12 mm, 16 mm, and 20mm.

Operation of the impedance catheter 39: With reference to the embodimentshown in FIG. 1B, the voltage difference between the detectionelectrodes 42 and 43 depends on the magnitude of the current, I,multiplied by the distance, D, between the detection electrodes anddivided by the conductivity, C, of the fluid and the cross-sectionalarea, CSA, of the artery or other organs into which the catheter isintroduced. Since the current, I, the distance, L, and the conductivity,C, normally can be regarded as calibration constants, an inverserelationship exists between the voltage difference and the CSA as shownby the following equations:

$\begin{matrix}{{{\Delta\; V} = \frac{I \cdot L}{C \cdot {CSA}}}{or}} & \left\lbrack {10a} \right\rbrack \\{{CSA} = \frac{G \cdot L}{C}} & \left\lbrack {10b} \right\rbrack\end{matrix}$where G is conductance expressed as the ratio of current to voltage,I/ΔV. Equation [10] is identical to Equation [1b] if the parallelconductance through the vessel wall is neglected and surrounding tissuebecause the balloon material acts as an insulator. This is thecylindrical model on which the conductance method is used.

As described below with reference to FIGS. 2A, 2B, 3, 4, and 5, theexcitation and detection electrodes are electrically connected toelectrically conductive leads in the catheter for connecting theelectrodes to the data acquisition system 100.

FIGS. 2A and 2B illustrate two embodiments 20A and 20B of the catheterin cross-section. Each embodiment has a lumen 60 for inflating anddeflating the balloon and a lumen 61 for suction and infusion. The sizesof these lumens can vary in size. The impedance electrode electricalleads 70A are embedded in the material of the catheter in the embodimentin FIG. 2A, whereas the electrode electrical leads 70B are tunneledthrough a lumen 71 formed within the body of catheter 70B in FIG. 2B.

Pressure conduits for perfusion manometry connect the pressure ports 90,91 to transducers included in the data acquisition system 100. As shownin FIG. 2A pressure conduits 95A may be formed in 20A. In anotherembodiment, shown in FIG. 2B, pressure conduits 95B constituteindividual conduits within a tunnel 96 formed in catheter 20B. In theembodiment described above where miniature pressure transducers arecarried by the catheter, electrical conductors will be substituted forthese pressure conduits.

With reference to FIG. 3, in one exemplary embodiment, the catheter 20connects to a data acquisition system 100, to a manual or automaticsystem 105 for distension of the balloon and to a system 106 forinfusion of fluid or suction of blood. The fluid will be heated to37-39° or equivalent to body temperature with heating unit 107. Theimpedance planimetry system typically includes a constant current unit,amplifiers and signal conditioners. The pressure system typicallyincludes amplifiers and signal conditioners. The system can optionallycontain signal conditioning equipment for recording of fluid flow in theorgan.

In one preferred embodiment, the system is pre-calibrated and the probeis available in a package. Here, the package also preferably containssterile syringes with the fluids to be injected. The syringes areattached to the machine and after heating of the fluid by the machineand placement of the probe in the organ of interest, the user presses abutton that initiates the injection with subsequent computation of thedesired parameters. The cross-sectional area, CSA, and parallelconductance, G_(p), and other relevant measures such as distensibility,tension, etc. will typically appear on the display panel in the PCmodule 160. Here, the user can then remove the stenosis by distension orby placement of a stent.

If more than one CSA is measured, the system can contain a multiplexerunit or a switch between CSA channels. In one embodiment, each CSAmeasurement will be through separate amplifier units. The same mayaccount for the pressure channels.

In one embodiment, the impedance and pressure data are analog signalswhich are converted by analog-to-digital converters 150 and transmittedto a computer 160 for on-line display, on-line analysis and storage. Inanother embodiment, all data handling is done on an entirely analogbasis. The analysis advantageously includes software programs forreducing the error due to conductance of current in the organ wall andsurrounding tissue and for displaying profile of the CSA distributionalong the length of the vessel along with the pressure gradient. In oneembodiment of the software, a finite element approach or a finitedifference approach is used to derive the CSA of the organ stenosistaking parameters such as conductivities of the fluid in the organ andof the organ wall and surrounding tissue into consideration. In anotherembodiment, simpler circuits are used; e.g., based on making two or moreinjections of different NaCl solutions to vary the resistivity of fluidin the vessel and solving the two simultaneous Equations [2] and [3] forthe CSA and parallel conductance (Equations [4] and [5], respectively).In another embodiment, the software contains the code for reducing theerror in luminal CSA measurement by analyzing signals duringinterventions such as infusion of a fluid into the organ or by changingthe amplitude or frequency of the current from the constant currentamplifier. The software chosen for a particular application, preferablyallows computation of the CSA with only a small error instantly orwithin acceptable time during the medical procedure.

In one approach, the wall thickness is determined from the parallelconductance for those organs that are surrounded by air ornon-conducting tissue. In such cases, the parallel conductance is equalto

$\begin{matrix}{G_{p} = \frac{{CSA}_{w} \cdot C_{w}}{L}} & \left\lbrack {11a} \right\rbrack\end{matrix}$where CSA_(w) is the wall area of the organ and C_(w) is the electricalconductivity through the wall. This equation can be solved for the wallCSA_(w) as

$\begin{matrix}{{CSA}_{w} = \frac{G_{p} \cdot L}{C_{w}}} & \left\lbrack {11b} \right\rbrack\end{matrix}$For a cylindrical organ, the wall thickness, h, can be expressed as

$\begin{matrix}{h = \frac{{CSA}_{w}}{\pi\; D}} & \lbrack 12\rbrack\end{matrix}$where D is the diameter of the vessel which can be determined from thecircular CSA (D=[4 CSA/π]^(1/2)).

When the CSA, pressure, wall thickness, and flow data are determinedaccording to the embodiments outlined above, it is possible to computethe compliance (e.g., ΔCSA/ΔP), tension (e.g., P·r, where P and r arethe intraluminal pressure and radius of a cylindrical organ), stress(e.g., P·r/h where h is the wall thickness of the cylindrical organ),strain (e.g., (C−C_(d))/C_(d) where C is the inner circumference andC_(d) is the circumference in diastole) and wall shear stress (e.g., 4μQ/r³ where μ, Q and r are the fluid viscosity, flow rate and radius ofthe cylindrical organ, respectively, for a fully developed flow). Thesequantities can be used in assessing the mechanical characteristics ofthe system in health and disease.

Exemplary Method

In one approach, luminal cross-sectional area is measured by introducinga catheter from an exteriorly accessible opening (e.g., mouth, nose, oranus for GI applications; or e.g., mouth or nose for airwayapplications) into the hollow system or targeted luminal organ. Forcardiovascular applications, the catheter can be inserted into theorgans in various ways; e.g., similar to conventional angioplasty. Inone embodiment, an 18 gauge needle is inserted into the femoral arteryfollowed by an introducer. A guide wire is then inserted into theintroducer and advanced into the lumen of the femoral artery. A 4 or 5Fr conductance catheter is then inserted into the femoral artery viawire and the wire is subsequently retracted. The catheter tip containingthe conductance electrodes can then be advanced to the region ofinterest by use of x-ray (i.e., fluoroscopy). In another approach, thismethodology is used on small to medium size vessels (e.g., femoral,coronary, carotid, iliac arteries, etc.).

In one approach, a minimum of two injections (with differentconcentrations and/or conductivities of NaCl) are required to solve forthe two unknowns, CSA and G_(p). In another approach, three injectionswill yield three set of values for CSA and G_(p) (although notnecessarily linearly independent), while four injections would yield sixset of values. In one approach, at least two solutions (e.g., 0.5% and1.5% NaCl solutions) are injected in the targeted luminal organ orvessel. Our studies indicate that an infusion rate of approximately 1ml/s for a five second interval is sufficient to displace the bloodvolume and results in a local pressure increase of less than 10 mmHg inthe coronary artery. This pressure change depends on the injection ratewhich should be comparable to the organ flow rate.

In one preferred approach, involving the application of Equations [4]and [5], the vessel is under identical or very similar conditions duringthe two injections. Hence, variables, such as, for example, the infusionrate, bolus temperature, etc., are similar for the two injections.Typically, a short time interval is to be allowed (1-2 minute period)between the two injections to permit the vessel to return to homeostaticstate. This can be determined from the baseline conductance as shown inFIG. 4 or 5. The parallel conductance is preferably the same or verysimilar during the two injections. In one approach, dextran, albumin oranother large molecular weight molecule can be added to the NaClsolutions to maintain the colloid osmotic pressure of the solution toreduce or prevent fluid or ion exchange through the vessel wall.

In one approach, the NaCl solution is heated to body temperature priorto injection since the conductivity of current is temperature dependent.In another approach, the injected bolus is at room temperature, but atemperature correction is made since the conductivity is related totemperature in a linear fashion.

In one approach, a sheath is inserted either through the femoral orcarotid artery in the direction of flow. To access the lower anteriordescending (LAD) artery, the sheath is inserted through the ascendingaorta. For the carotid artery, where the diameter is typically on theorder of 5-5.5 mm, a catheter having a diameter of 1.9 mm can be used,as determined from finite element analysis, discussed further below. Forthe femoral and coronary arteries, where the diameter is typically inthe range from 3.5-4 mm, so a catheter of about 0.8 mm diameter would beappropriate. The catheter can be inserted into the femoral, carotid orLAD) artery through a sheath appropriate for the particular treatment.Measurements for all three vessels can be made similarly.

Described here are the protocol and results for one exemplary approachthat is generally applicable to most arterial vessels. The conductancecatheter was inserted through the sheath for a particular vessel ofinterest. A baseline reading of voltage was continuously recorded. Twocontainers containing 0.5% and 1.5% NaCl were placed in temperature bathand maintained at 37°. A 5-10 ml injection of 1.5% NaCl was made over a5 second interval. The detection voltage was continuously recorded overa 10 second interval during the 5 second injection. Several minuteslater, a similar volume of 1.5% NaCl solution was injected at a similarrate. The data was again recorded. Matlab was used to analyze the dataincluding filtering with high pass and with low cut off frequency (1200Hz). The data was displayed using Matlab and the mean of the voltagesignal during the passage of each respective solution was recorded. Thecorresponding currents were also measured to yield the conductance,G=I/V. The conductivity of each solution was calibrated with sixdifferent tubes of known CSA at body temperature. A model using Equation[10] was fitted to the data to calculate conductivity C. The analysiswas carried out in SPSS using the non-linear regression fit. Given C andG for each of the two injections, an excel sheet file was formatted tocalculate the CSA and G_(p) as per Equations [4] and [5], respectively.These measurements were repeated several times to determine thereproducibility of the technique. The reproducibility of the data waswithin 5%. Ultrasound (US) was used to measure the diameter of thevessel simultaneous with our conductance measurements. The detectionelectrodes were visualized with US and the diameter measurements wasmade at the center of the detection electrodes. The maximum differencesbetween the conductance and US measurements were within 10%.

FIGS. 4A, 4B, 5A and 5B illustrate voltage measurements in the bloodstream in the left carotid artery. Here, the data acquisition had a thesampling frequency of 75 KHz, with two channels—the current injected andthe detected voltage, respectively. The current injected has a frequencyof 5 KHz, so the voltage detected, modulated in amplitude by theimpedance changing through the bolus injection will have a spectrum inthe vicinity of 5 KHz.

With reference to FIG. 4A, there is shown a signal processed with a highpass filter with low cut off frequency (1200 Hz). The top and bottomportions 200, 202 show the peak-to-peak envelope detected voltage whichis displayed in FIG. 4B (bottom). The initial 7 seconds correspond tothe baseline; i.e., electrodes in the blood stream. The next 7 secondscorrespond to an injection of hyper-osmotic NaCl solution (1.5% NaCl).It can be seen that the voltage is decreased implying increaseconductance (since the injected current is constant). Once the NaClsolution is washed out, the baseline is recovered as can be seen in thelast portion of the FIGS. 4A and 4B. FIGS. 5A and 5B shows similar datacorresponding to 0.5% NaCl solutions.

The voltage signals are ideal since the difference between the baselineand the injected solution is apparent and systematic. Furthermore, thepulsation of vessel diameter can be seen in the 0.5% and 1.5% NaClinjections (FIGS. 4 and 5, respectively). This allows determination ofthe variation of CSA throughout the cardiac cycle as outline above.

The NaCl solution can be injected by hand or by using a mechanicalinjector to momentarily displace the entire volume of blood or bodilyfluid in the vessel segment of interest. The pressure generated by theinjection will not only displace the blood in the antegrade direction(in the direction of blood flow) but also in the retrograde direction(momentarily push the blood backwards). In other visceral organs whichmay be normally collapsed, the NaCl solution will not displace blood asin the vessels but will merely open the organs and create a flow of thefluid. In one approach, after injection of a first solution into thetreatment or measurement site, sensors monitor and confirm baseline ofconductance prior to injection of a second solution into the treatmentsite.

The injections described above are preferably repeated at least once toreduce errors associated with the administration of the injections, suchas, for example, where the injection does not completely displace theblood or where there is significant mixing with blood. It will beunderstood that any bifurcation(s) (with branching angle near 90degrees) near the targeted luminal organ can cause an overestimation ofthe calculated CSA. Hence, generally the catheter should be slightlyretracted or advanced and the measurement repeated. An additionalapplication with multiple detection electrodes or a pull back or pushforward during injection will accomplish the same goal. Here, an arrayof detection electrodes can be used to minimize or eliminate errors thatwould result from bifurcations or branching in the measurement ortreatment site.

In one approach, error due to the eccentric position of the electrode orother imaging device can be reduced by inflation of a balloon on thecatheter. The inflation of balloon during measurement will place theelectrodes or other imaging device in the center of the vessel away fromthe wall. In the case of impedance electrodes, the inflation of ballooncan be synchronized with the injection of bolus where the ballooninflation would immediately precede the bolus injection. Our results,however, show that the error due to catheter eccentricity is small.

The CSA predicted by Equation [4] corresponds to the area of the vesselor organ external to the catheter (i.e., CSA of vessel minus CSA ofcatheter). If the conductivity of the NaCl solutions is determined bycalibration from Equation [10] with various tubes of known CSA, then thecalibration accounts for the dimension of the catheter and thecalculated CSA corresponds to that of the total vessel lumen as desired.In one embodiment, the calibration of the CSA measurement system will beperformed at 37° C. by applying 100 mmHg in a solid polyphenolenoxideblock with holes of known CSA ranging from 7.065 mm² (3 mm in diameter)to 1.017 mm² (36 mm in diameter). If the conductivity of the solutionsis obtained from a conductivity meter independent of the catheter,however, then the CSA of the catheter is generally added to the CSAcomputed from Equation [4] to give the desired total CSA of the vessel.

The signals are generally non-stationary, nonlinear and stochastic. Todeal with non-stationary stochastic functions, one can use a number ofmethods, such as the Spectrogram, the Wavelet's analysis, theWigner-Ville distribution, the Evolutionary Spectrum, Modal analysis, orpreferably the intrinsic model function (IMF) method. The mean orpeak-to-peak values can be systematically determined by theaforementioned signal analysis and used in Equation [4] to compute theCSA.

Exemplary Four-Injection Approach

In at least one method of the disclosure of the present application, afour-injection approach is provided. As previously disclosed herein, twoinjections provide the cross-sectional area, CSA, and parallelconductance, G_(p), at a particular point.

In at least one approach, four injections are provided to determineparallel conductance at multiple points. In an exemplary study, fourinjections may be performed to determine a segment of 2-3 cm long orlonger. In this study, two injections may be performed at the distal endof the segment, and two injections may be performed at the proximal endof the segment. The two injections may deliver, for example, a volume of1.5% NaCl and a volume of 0.5% NaCl, at each end of the segment, notingthat any number of solutions, volumes, and concentrations thereofsuitable for such a study, or for the other studies contemplated by thedisclosure of the present application, could be utilized. For example,solutions having different salinities can be introduced in variousphysiological saline solutions (PSS) or in a Kreb solution containingother ions such as potassium, sodium, etc. In this exemplary study, thefirst two injections (1.5% NaCl and 0.5% NaCl) may be made at the distalpoint of the segment, and the catheter system would then be pulled backto the proximal point of the segment, whereby two more injections (1.5%NaCl and 0.5% NaCl) may be made, with conductance values taken at thedistal end and the proximal end of the segment used to determine theentire profile of the segment.

As referenced herein with respect to Equation [1a], conductance may becalculated taking into account cross-sectional area, electricalconductivity of a fluid, and effective conductance of a structure. Whenperforming a study as described above, the two end points (proximal anddistal ends of a segment) are clearly exact, and an intermediate profilebetween those two points can be derived based upon the analysis providedherein. Since the cross-sectional area, CSA, and parallel conductance ata point, G_(p), are known at each of the two ends of a segment, thecorresponding blood conductivity may be calculated:

$\begin{matrix}{G_{Total} = {\frac{{CSA} \cdot C_{b}}{L} + G_{p}}} & \lbrack 13\rbrack\end{matrix}$where G_(Total) is the total conductance (current divided by voltage),CSA is the cross-sectional area, C_(b) is the blood conductivity, L isthe detection electrode spacing on the catheter, and G_(p) is theparallel conductance at a point. The mean of the two values may then becalculated based upon the foregoing.

A procedure as described above may be accomplished, for example, byperforming the following steps:

-   -   Step 1: Calculate total conductance (G_(Total), current divided        by voltage, or I/V, where I is the current injected and V is the        voltage recorded) for two ends (proximal and distal) of a        segment.    -   Step 2: Calculate the Coeff ratio (cross-sectional area divided        by total conductance, or CSA/G_(Total)) at the two ends of the        segment.    -   Step 3: Linearly interpolate along the length of the pull back        for the Coeff, so that the two ends of the segment have the same        Coeffs calculated from Step 2 above.    -   Step 4: Calculate total conductance (G_(Total)) for the entire        length of the pull back (distance between the two ends of the        segment).    -   Step 5: At each point calculated in the pull back, multiply the        total conductance (G_(Total)) times its respective Coeff. The        product of this calculation is the cross-sectional area (CSA).    -   Step 6: Determine the diameter from the cross-sectional area        (CSA) along the entire profile.

A mathematical explanation of the concept referenced in the procedureabove is as follows. First, the equation governing the physics ofelectrical conductance has the following form:

$\begin{matrix}{G_{Total} = {\frac{I}{V} = {\frac{{CSA} \cdot \sigma}{L} + G_{p}}}} & \lbrack 14\rbrack\end{matrix}$where G_(Total) is the total conductance, I is the current, V is thevoltage, CSA is the cross-sectional area, σ is the conductivity of thefluid, L is the detection electrode spacing on the catheter, and G_(p)is the parallel conductance at a point.

Experimentation as shown that parallel conductance (G_(p)) is linearlyrelated to cross-sectional area, with a negative slope. For example, alarger CSA has a smaller G_(p). As such, G_(p) can be replaced with alinear function of CSA as follows:

$\begin{matrix}{G_{Total} = {\frac{I}{V} = {\frac{{CSA} \cdot \sigma}{L} + {m \cdot {CSA}} + b}}} & \lbrack 15\rbrack\end{matrix}$where G_(Total) is the total conductance, I is the current, V is thevoltage, CSA is the cross-sectional area, σ is the conductivity of thefluid, L is the detection electrode spacing on the catheter, m is theslops, and b is the intercept as can be determined for a linear leastsquare fit. This may be rearranged as follows:

$\begin{matrix}{G_{Total} = {{\left( {\frac{\sigma}{L} + m} \right){CSA}} + b}} & \lbrack 16\rbrack\end{matrix}$

It is shown that total conductance (G_(Total)) is clearly linearlyrelated to cross-sectional area (CSA). If the coefficient b is ignored(wherein b should be equal to zero if CSA is equal to zero), then wehave the following:

$\begin{matrix}{\left( \frac{CSA}{G_{Total}} \right) = {Coeff}} & \lbrack 17\rbrack\end{matrix}$

The Coeff value at both ends of a segment can be found where the twoinjections are made, and those values may then be used to linearlyinterpolate across the profile. Once a Coeff value for every point inthe pull back is determined, those Coeff values are multiplied by theirrespective G_(Total) values to determine the CSA values along theprofile, namely:

$\begin{matrix}{{{CSA} = {{Coeff}*G_{Total}}}{and}} & \lbrack 18\rbrack \\{{Diameter} = \sqrt{\frac{4*{CSA}}{\pi}}} & \lbrack 19\rbrack\end{matrix}$to determine a diameter.Exemplary Three-Injection Approach

In at least one method of the disclosure of the present application, athree-injection approach to determine a profile as outlined above withrespect to the four-injection approach is also provided. In at least oneapproach, three injections are provided, with two injections at thedistal end of a segment, simultaneous withdrawal of one of the injectionsources, and one injection at the proximal end of the segment.

In an exemplary study, the first two injections at the distal end maydeliver, for example, a volume of 1.5% NaCl and a volume of 0.5% NaCl,noting that any number of solutions, volumes, and concentrations thereofsuitable for such a study could be utilized. In this exemplary study,the first two injections (1.5% NaCl and 0.5% NaCl) may be made at thedistal point of the segment, wherein the catheter system issimultaneously withdrawn with the injection of the 0.5% NaCl so that the0.5% NaCl may also be used for the proximal end. These injections wouldthen be followed by a 1.5% NaCl injection at the proximal end of thesegment.

Advantages to this particular approach over the four-injection approachare that (1) the conductivity would be simplified as that of 0.5% ratherthan blood, and (2) there are only three injections required instead offour. However, the three-injection method also requires that a physicianusing a catheter system to perform such a procedure would be required toinject and pull back simultaneously. A physician comfortable withsimultaneous injection and pull back may prefer the three-injectionapproach, while a physician not comfortable with simultaneous injectionand pull back may prefer the four-injection approach. Either approach ispossible using the algorithm provided herein.

Ex-Vivo and In-Vivo Validation of Algorithm

Studies were performed ex-vivo in in-vivo to validate the algorithmprovided herein. The former was validated in a carotid artery with anartificial stenosis to compare the algorithm disclosed herein versuscast measurements for both for the two-injection method at severaldiscrete points and the reconstructed profile. The latter validation wasdone in vivo in a coronary artery (LAD) where a comparison between LR(LumenRecon) and IVUS (intravascular) was made.

Ex-Vivo Validation of Algorithm

To validate the algorithm ex-vivo, a segment of a swine carotid arterywas removed and mounted on a bench stand as shown in FIG. 9. A smallportion of one end of the vessel was removed and used to create astenosis around the vessel, which was accomplished by wrapping thispiece of tissue around the middle of the vessel and shortening the pieceof tissue using suture. A black indicator was used to mark the outsideof the vessel at six locations along the length (length=3.23 cm). Asshown in FIG. 9, the bottom portion of the vessel is the distal end, andblack marks signify where LumenRecon measurements were made using atwo-injection method of the present disclosure.

The LumenRecon system was calibrated using the 0.45% and 1.5% salineconcentrations. A two-injection method according to the presentdisclosure was used to make single diameter measurements at the sixlocations along the length of the vessel. “Pull back” measurements werealso made along the length of the vessel to create a continuous profileof the vessel diameter.

After the LumenRecon measurements were taken, a cast mold of the vesselwas created. The diameter of the cast mold of the vessel was determinedusing microscopy. The cast measurements were taken at the six locationsmarked by the black indicator and at intermediate locations along thevessel.

The diameters from the LumenRecon two injection method and the pull backmeasurements were plotted against the cast measurements, respectively.FIG. 10 shows the data for the six locations using a two-injectionmethod of the present disclosure, comparing the diameters calculated bythe LumenRecon system to those measured from the cast mold of the vesselusing microscopy. The least square fit of the data showsy=1.0599x−0.1805, R²=0.9944. FIG. 11 shows a profile of data points(diameters) using a pull back method of the present disclosure,comparing the diameters calculated by the LumenRecon system to thosemeasured from the cast mold of the vessel using microscopy.

In Vivo Validation

The LumenRecon system was used to make measurements in the left anteriordescending (LAD) coronary artery in an anesthetized swine. Atwo-injection method of the present disclosure was used to construct aprofile which was compared to IVUS at four different locations along theprofile. FIG. 12 shows the LumenRecon measurements plotted against theIVUS measurements, showing the measurements before and after thetemperature correction. The temperature correction was incorporated intothe calibration of the catheter. It was determined that a NaCl solutioninjected at room temperature (25° C.) reaches 30° C. when at the bodysite of measurement (39° C.). Hence, calibrations of fluid were made at30° C. to account for the heating of the fluid during injection.

Phasic Changes of Vessel Lumen Area

As discussed above and herein, an exemplary two-injection method mayprovide the mean CSA and G_(p) at any particular point. Equation [14],as described in detail above, provides the equation governing thephysics of electrical conductance as applied to CSA, fluid conductivity,and parallel conductance. At a fixed spatial position in a vessel, themean conductivity of blood, σ_(b), can then be determined from Equation[14] as follows:

$\begin{matrix}{{\overset{\_}{\sigma}}_{b} = {\frac{L}{\overset{\_}{CSA}}\left\lbrack {{G_{Total}(t)} - \overset{\_}{G_{p}}} \right\rbrack}} & \lbrack 20\rbrack\end{matrix}$wherein σ_(b) is the mean conductivity of blood, L is the detectionelectrode spacing on a catheter, CSA is the mean cross-sectional area,G_(Total)(t) is the total conductance at a given time, and G_(p) is themean parallel conductance. In at least one embodiment, and in asituation where only one parallel conductance value is known, the valueof the parallel conductance value may be substituted in place of a meanparallel tissue conductance value.

As blood conductivity only varies by approximately ten percent (10%)through the cardiac cycle, blood conductivity, for the purposesdescribed herein, may also be considered as a constant having a meanvalue. Hence, the phasic change of CSA (at any given location) duringthe cardiac cycle can be calculated by the following equation:

$\begin{matrix}{{{CSA}(t)} = {\frac{L}{\overset{\_}{\sigma_{b}}}\left\lbrack {{G_{Total}(t)} - \overset{\_}{G_{p}}} \right\rbrack}} & \lbrack 21\rbrack\end{matrix}$

wherein CSA(t) is the phasic change in cross-sectional area, L is thedetection electrode spacing on a catheter, σ_(b) is the meanconductivity of blood, G_(Total)(t) is the total conductance at a giventime, and G_(p) is the mean parallel conductance.

The temporal changes of CSA, or diameter derived therefrom as referencedherein, can be determined from the phasic changes of total conductance.For example, conductance data as shown in FIG. 13A, can be converted toCSA or diameter of the artery as outlined above. FIG. 13A shows thephasic changes of total conductance showing cardiac and respiratorychanges, with the narrow tall peaks representing detected heart rate,and the sinusoidal wave (approximately three and one half wavelengthsshown) represents respiratory changes (inhalation and exhalation).

The phasic changes of diameters of a normal coronary artery (FIG. 13B)or an atherosclerotic coronary artery (FIG. 13C) are shown throughoutseveral cardiac cycles. FIG. 13B shows the phasic changes of a “normal”blood vessel (without any sort of stenosis or lesion) having a similarprofile to the profile shown in FIG. 13A. The cardiac as well asrespiratory changes of coronary diameter are apparent for the normalanimal. FIG. 13C shows the same parameters (changes in diameter of avessel over time) shown in FIG. 13B, but instead of a “normal” vessel,the results are reflective of a diseased (atherosclerotic) vessel. Asshown in FIG. 13C, only changes in vessel diameter due to the cardiaccycle are shown, noting that respiration has no visible impact on vesseldiameter of this exemplary diseased vessel (noting that the respiratorychanges for the conductance data vanish in the atherosclerotic animals).

The phasic changes of blood vessel shown in FIGS. 13A-13C have clinicalimportance. A healthy vessel, for example, will show significant changesin vessel diameter through the cardiac cycle as shown in FIG. 13B. Acalcified vessel, on the other hand, will show no changes in diameterthrough the cardiac cycle as shown in FIG. 13C. A decrease in compliance(or increase in stiffness) of vessels has been well established withvascular disease.

The compliance of a vessel determined by the change of CSA per change ofpressure through the cardiac cycle is described as follows:C=ΔCSA/ΔP  [22]wherein C is vessel compliance, ΔCSA is the change of cross-sectionalarea, and ΔP is the change in pressure through the cardiac cycle.Alternatively, since the ΔP is relatively constant for various patients,an index of compliance can be expressed as%ΔCSA=(CSA_(systolic)−CSA_(diastolic))/CSA_(diastolic)×100  [23]wherein % ΔCSA is the index of compliance, CSA_(systolic) is thecross-sectional area of a vessel during systole, and CSA_(diastolic) isthe cross-sectional area of a vessel during diastole. Similarly,Equations [22] and [23] can be expressed in terms of diameter, whereinvalues for cross-sectional area are replaced with values for diameter.

Such relations, as described herein, can be used to determine a phasicchange or the compliance of the vessel and hence the degree of vasculardisease. For example, if a vessel is deemed to have relatively lowcompliance or have a relatively low calculated phasic change in diameteror cross-sectional area, the extent of vessel disease may be determinedto be relatively high. Conversely, and for example, if a vessel isdeemed to have relatively high compliance or have a relatively highcalculated phasic change in diameter or cross-sectional area, the extentof vessel disease may be determined to be relatively low. Currently, noother imaging method, including, but not limited to, angiography orIVUS, has the temporal resolution to provide the phasic changesthroughout the cardiac cycle in real-time as referenced herein.

Referring to the embodiment shown in FIG. 6, the angioplasty balloon 30is shown distended within the coronary artery 150 for the treatment ofstenosis. As described above with reference to FIG. 1B, a set ofexcitation electrodes 40, 41 and detection electrodes 42, 43 are locatedwithin the angioplasty balloon 30. In another embodiment, shown in FIG.7, the angioplasty balloon 30 is used to distend the stent 160 withinblood vessel 150.

For valve area determination, it is not generally feasible to displacethe entire volume of the heart. Hence, the conductivity of blood ischanged by injection of hypertonic NaCl solution into the pulmonaryartery which will transiently change the conductivity of blood. If themeasured total conductance is plotted versus blood conductivity on agraph, the extrapolated conductance at zero conductivity corresponds tothe parallel conductance. In order to ensure that the two innerelectrodes are positioned in the plane of the valve annulus (2-3 mm), inone preferred embodiment, the two pressure sensors 36 are advantageouslyplaced immediately proximal and distal to the detection electrodes (1-2mm above and below, respectively) or several sets of detectionelectrodes (see, e.g., FIGS. 1D and 1F). The pressure readings will thenindicate the position of the detection electrode relative to the desiredsite of measurement (aortic valve: aortic-ventricular pressure; mitralvalve: left ventricular-atrial pressure; tricuspid valve: rightatrial-ventricular pressure; pulmonary valve: rightventricular-pulmonary pressure). The parallel conductance at the site ofannulus is generally expected to be small since the annulus consistsprimarily of collagen which has low electrical conductivity. In anotherapplication, a pull back or push forward through the heart chamber willshow different conductance due to the change in geometry and parallelconductance. This can be established for normal patients which can thenbe used to diagnose valvular stenosis.

In one approach, for the esophagus or the urethra, the procedures canconveniently be done by swallowing fluids of known conductances into theesophagus and infusion of fluids of known conductances into the urinarybladder followed by voiding the volume. In another approach, fluids canbe swallowed or urine voided followed by measurement of the fluidconductances from samples of the fluid. The latter method can be appliedto the ureter where a catheter can be advanced up into the ureter andfluids can either be injected from a proximal port on the probe (willalso be applicable in the intestines) or urine production can beincreased and samples taken distal in the ureter during passage of thebolus or from the urinary bladder.

In one approach, concomitant with measuring the cross-sectional area andor pressure gradient at the treatment or measurement site, a mechanicalstimulus is introduced by way of inflating the balloon or by releasing astent from the catheter, thereby facilitating flow through the stenosedpart of the organ. In another approach, concomitant with measuring thecross-sectional area and or pressure gradient at the treatment site, oneor more pharmaceutical substances for diagnosis or treatment of stenosisis injected into the treatment site. For example, in one approach, theinjected substance can be smooth muscle agonist or antagonist. In yetanother approach, concomitant with measuring the cross-sectional areaand or pressure gradient at the treatment site, an inflating fluid isreleased into the treatment site for release of any stenosis ormaterials causing stenosis in the organ or treatment site.

Again, it will be noted that the methods, systems, and devices describedherein can be applied to any body lumen or treatment site. For example,the methods, systems, and devices described herein can be applied to anyone of the following exemplary bodily hollow systems: the cardiovascularsystem including the heart; the digestive system; the respiratorysystem; the reproductive system; and the urogenital tract.

Finite Element Analysis: In one preferred approach, finite elementanalysis (FEA) is used to verify the validity of Equations [4] and [5].There are two major considerations for the model definition: geometryand electrical properties. The general equation governing the electricscalar potential distribution, V, is given by Poisson's equation as:∇·(C∇V)=−I  [24]where C, I, and ∇ are the conductivity, the driving current density, andthe del operator, respectively. Femlab or any standard finite elementpackages can be used to compute the nodal voltages using Equation [24].Once V has been determined, the electric field can be obtained from asE=−∇V.

The FEA allows the determination of the nature of the field and itsalteration in response to different electrode distances, distancesbetween driving electrodes, wall thicknesses and wall conductivities.The percentage of total current in the lumen of the vessel, % I, can beused as an index of both leakage and field homogeneity. Hence, thevarious geometric and electrical material properties can be varied toobtain the optimum design; i.e., minimize the non-homogeneity of thefield. Furthermore, the experimental procedure was simulated byinjection of the two solutions of NaCl to verify the accuracy ofEquation [4]. Finally, an assessment of the effect of presence ofelectrodes and catheter in the lumen of vessel may be performed. Theerror terms representing the changes in measured conductance due to theattraction of the field to the electrodes and the repulsion of the fieldfrom the resistive catheter body were quantified.

Poisson's equation for the potential field was solved, taking intoaccount the magnitude of the applied current, the location of thecurrent driving and detection electrodes, and the conductivities andgeometrical shapes in the model including the vessel wall andsurrounding tissue. This analysis suggest that the following conditionsare optimal for the cylindrical model: (1) the placement of detectionelectrodes equidistant from the excitation electrodes; (2) the distancebetween the current driving electrodes should be much greater than thedistance between the voltage sensing electrodes; and (3) the distancebetween the detection and excitation electrodes is comparable to thevessel diameter or the diameter of the vessel is small relative to thedistance between the driving electrodes. If these conditions aresatisfied, the equipotential contours more closely resemble straightlines perpendicular to the axis of the catheter and the voltage dropmeasured at the wall will be nearly identical to that at the center.Since the curvature of the equipotential contours is inversely relatedto the homogeneity of the electric field, it is possible to optimize thedesign to minimize the curvature of the field lines. Consequently, inone preferred approach, one or more of conditions (1)-(3) describedabove are met to increase the accuracy of the cylindrical model.

Theoretically, it is impossible to ensure a completely homogeneous fieldgiven the current leakage through the vessel wall into the surroundingtissue. Research leading to the disclosure of the present applicationidentified that the isopotential line is not constant as one moves outradially along the vessel as stipulated by the cylindrical model. In oneembodiment, a catheter with a radius of 0.55 mm is considered whosedetected voltage is shown in FIGS. 8A and 8B for two different NaClsolutions (0.5% and 1.5%, respectively). The origin corresponds to thecenter of the catheter. The first vertical line 220 represents the innerpart of the electrode which is wrapped around the catheter and thesecond vertical line 221 is the outer part of the electrode in contactwith the solution (diameter of electrode is approximately 0.25 mm). Thesix different curves, top to bottom, correspond to six different vesselswith radii of 3.1, 2.7, 2.3, 1.9, 1.5, and 0.55 mm, respectively. It canbe seen that a “hill” occurs at the detection electrode 220, 221followed by a fairly uniform plateau in the vessel lumen followed by anexponential decay into the surrounding tissue. Since the potentialdifference is measured at the detection electrode 220, 221, thesimulation generates the “hill” whose value corresponds to theequivalent potential in the vessel as used in Eq. [4]. Hence, for eachcatheter size, the dimension of the vessel was varied such that equation[4] is exactly satisfied. Consequently, the optimum catheter size for agiven vessel diameter was obtained such that the distributive modelsatisfies the lumped equations (Equation [4] and [5]). In this way, arelationship between vessel diameter and catheter diameter may begenerated such that the error in the CSA measurement is less than 5%.

In an exemplary embodiment, different diameter catheters are prepackagedand labeled for optimal use in certain size vessel. For example, forvessel dimension in the range of 4-5 mm, 5-7 mm or 7-10 mm, analysis inaccordance with the disclosure of the present application shows that theoptimum diameter catheters will be in the range of 0.9-1.4, 1.4-2.0 or2.0-4.6 mm, respectively. A clinician can select the appropriatediameter catheter based on the estimated vessel diameter of interest.This decision will be made prior to the procedure and will serve tominimize the error in the determination of lumen CSA.

It can be appreciated that any number of devices may be used inaccordance within the scope of the present disclosure, including, butnot limited to, any number of catheters and/or wires. In exemplaryembodiments, catheters, including, but not limited to, impedance and/orguide catheters, and wires, including, but not limited to, impedancewires, guide wires, pressure wires, and flow wires, may be used asappropriate as devices, systems, and/or portions of systems of thepresent disclosure, and may be used as appropriate to perform one ormore methods, or steps thereof, of the present disclosure.

While various embodiments of systems and methods for determining aphasic change in a vessel and vessel compliance have been described inconsiderable detail herein, the embodiments are merely offered by way ofnon-limiting examples of the disclosure described herein. Manyvariations and modifications of the embodiments described herein will beapparent to one of ordinary skill in the art in light of thisdisclosure. It will therefore be understood by those skilled in the artthat various changes and modifications may be made, and equivalents maybe substituted for elements thereof, without departing from the scope ofthe disclosure. Indeed, this disclosure is not intended to be exhaustiveor to limit the scope of the disclosure. The scope of the disclosure isto be defined by the appended claims, and by their equivalents.

Further, in describing representative embodiments, the disclosure mayhave presented a method and/or process as a particular sequence ofsteps. However, to the extent that the method or process does not relyon the particular order of steps set forth herein, the method or processshould not be limited to the particular sequence of steps described. Asone of ordinary skill in the art would appreciate, other sequences ofsteps may be possible. Therefore, the particular order of the stepsdisclosed herein should not be construed as limitations on the claims.In addition, the claims directed to a method and/or process should notbe limited to the performance of their steps in the order written, andone skilled in the art can readily appreciate that the sequences may bevaried and still remain within the spirit and scope of the presentdisclosure.

It is therefore intended that the disclosure will include, and thisdescription and the appended claims will encompass, all modificationsand changes apparent to those of ordinary skill in the art based on thisdisclosure.

1. A method for determining vessel compliance, the method comprising the steps of: introducing a device into a site within a vessel, the device comprising: a pair of excitation electrodes positioned along a portion of the device; and a pair of detection electrodes positioned along a portion of the device, the pair of detection electrodes comprising two detection electrodes having a known distance from one another, the pair of detection electrodes physically positioned in between the pair of excitation electrodes; operating the device in connection with two or more fluid injections in the vessel at or near the site to obtain two or more conductance values, each of the two or more fluid injections having a known conductivity; calculating a first vessel parameter of the site based on at least two of the two or more conductance values and the conductivities of at least two of the two or more fluid injections; calculating a second vessel parameter of the site based on at least two of the two or more conductance values and the conductivities of at least two of the two or more fluid injections; calculating a change in vessel parameter based upon the first vessel parameter and the second vessel parameter; calculating vessel compliance based upon the relationship between the change in vessel parameter and a change in pressure during a cardiac cycle; and calculating an index of compliance based in part upon a difference between the first vessel parameter and the second vessel parameter divided by the first vessel parameter.
 2. The method of claim 1, further comprising the step of: determining the extent of vessel disease based upon the calculated vessel compliance.
 3. The method of claim 2, wherein the extent of vessel disease is determined to be relatively low if the calculated vessel compliance is relatively high.
 4. The method of claim 2, wherein the extent of vessel disease is determined to be relatively high if the calculated vessel compliance is relatively low.
 5. The method of claim 2, wherein the extent of vessel disease is determined to include vessel calcification if the calculated vessel compliance is zero.
 6. The method of claim 2, wherein the extent of vessel disease includes a vessel disease selected from the group consisting of atherosclerosis, vessel calcification, degenerative calcific disease, congenital heart disease, rheumatic disease, and coronary artery disease.
 7. The method of claim 1, wherein the two or more conductance values are retrieved by a data acquisition and processing system operably connected to the device, and wherein the data acquisition and processing system is operable to calculate vessel compliance.
 8. The method of claim 1, wherein the change in pressure during a cardiac cycle has a constant value for a patient.
 9. The method of claim 1, wherein the first vessel parameter and the second vessel parameter each comprise a vessel diameter, and wherein the change in vessel parameter comprises a change in vessel diameter.
 10. The method of claim 1, wherein the first vessel parameter and the second vessel parameter each comprise a vessel cross-sectional area, and wherein the change in vessel parameter comprises a change in vessel cross-sectional area.
 11. The method of claim 1, wherein the first vessel parameter comprises a first vessel systolic diameter, wherein the second vessel parameter comprises a second vessel diastolic diameter, and wherein the first vessel systolic diameter and the second vessel diastolic diameter are representative of a single vessel.
 12. The method of claim 1, wherein the first vessel parameter comprises a first vessel systolic cross-sectional area, wherein the second vessel parameter comprises a second vessel diastolic cross-sectional area, and wherein the first vessel systolic cross-sectional area and the second vessel diastolic cross-sectional area are representative of a single vessel.
 13. The method of claim 1, wherein the device comprises a device selected from the group consisting of an impedance catheter, a guide catheter, a guide wire, and a pressure wire.
 14. The method of claim 1, wherein the device further comprises an inflatable balloon positioned along a portion of the device, and wherein the method further comprises the step of inflating the balloon to breakup materials causing stenosis at the site.
 15. The method of claim 14, wherein the device further comprises a stent positioned over the balloon, the stent capable of being distended to a desired size and implanted into the site, and wherein the method further comprises the steps of: distending the stent by inflating the balloon; and releasing and implanting the stent into the site.
 16. The method of claim 15, wherein the balloon is inflated using a fluid, and wherein the method further comprises the steps of: providing electrical current to the fluid filling the balloon at various degrees of balloon distension; measuring a conductance of the fluid inside the balloon; and calculating a cross-sectional area of the balloon lumen.
 17. The method of claim 1, wherein the device comprises at least one suction/infusion port in communication with at least one lumen of the device, whereby the two or more fluid injections occur via the at least one suction/infusion port.
 18. A method for determining vessel compliance, the method comprising the steps of: introducing a device into a site within a vessel, the device comprising a pair of excitation electrodes and a pair of detection electrodes positioned therebetween; operating the device to obtain two or more conductance values; calculating a change in cross-sectional area based in part upon the two or more conductance values; calculating vessel compliance based upon the relationship between the change in cross-sectional area and a change in pressure during a cardiac cycle; and calculating an index of compliance based in part upon a difference between the first vessel parameter and the second vessel parameter divided by the first vessel parameter.
 19. A system for determining vessel compliance, the system comprising: a device capable of acquiring conductance data, the device comprising: a pair of excitation electrodes positioned along a portion of the device; and a pair of detection electrodes positioned along a portion of the device, the pair of detection electrodes comprising two detection electrodes having a known distance from one another, the pair of detection electrodes physically positioned in between the pair of excitation electrodes along a portion of the device; an injection source for injecting one or more solutions through the device to a target site; a current source for providing current to the device; and a data acquisition and processing system that receives conductance data from the device, wherein the data acquisition and processing system is operable to calculate vessel compliance based upon: a. a calculated change in vessel parameter based upon a calculated first vessel parameter and a calculated second vessel parameter, the calculated first vessel parameter and a calculated second vessel parameter calculated based upon the conductance data acquired from the device; and b. a calculated relationship between the calculated change in vessel parameter and a change in pressure during a cardiac cycle; wherein the data acquisition and processing system is further operable to calculate an index of compliance based in part upon a difference between the first vessel parameter and the second vessel parameter divided by the first vessel parameter. 